Experts Serve Up Guidelines for IgG4-related Disease

Clinical history and a physical exam should dictate further testing.

Action Points

Accurate assessment of IgG4-related disease (IgG4-RD), an immune-mediated fibroinflammatory condition, requires a full clinical history, physical examination, selected laboratory investigations and appropriate radiology studies, according to an international expert panel.

Measurements of serum IgG4 concentrations are important in the evaluation and longitudinal assessment of patients but elevated levels are neither necessary nor sufficient for the diagnosis of IgG4-RD.

The most accurate assessment of IgG4-related disease (IgG4-RD) is based on a full clinical history, physical examination, selected laboratory investigations and appropriate radiology studies. That's the first and foremost position issued by a panel of experts who were invited to participate in the Second International Symposium on IgG4-RD and associated conditions in 2014.

In preparation for the symposium, 42 IgG4-RD experts were asked to participate in a consensus exercise and develop management guidelines for patients with IgG4-RD; 38 invitees participated in all parts of the process.

Almost all members of the panel concurred that a thorough clinical history must guide the initial evaluation of a patient with possible IgG-RD,

However, "neither clinical nor pathologic findings alone are sufficient to diagnosis IgG4-RD in most cases," lead author Arezou Khosroshahi, MD, Emory University School of Medicine, Atlanta, Georgia and colleagues write in Arthritis & Rheumatology.

As panel members point out, a variety of diseases can be mistaken for IgG4-RD and the list of disorders that needs to be considered varies by organ involvement.

The correct diagnosis is therefore most effectively arrived at by having both clinicians and pathologists review and discuss clinical features and pathologic findings as conditions that can mimic IgG4-RD clinically and histopathologically are extremely diverse.

Measurements of serum IgG4 concentrations remain important in the evaluation and longitudinal assessment of patients with possible IgG4-RD, panel members add.

But here again, "elevated levels [of serum IgG4] are neither necessary nor sufficient for the diagnosis of IgG4-RD," they stress, as elevated serum IgG4 concentrations have been observed in patients with a variety of other disorders, making serum IgG4 concentrations a poor stand-alone diagnostic test for the condition.

In some patients, complement levels are a helpful indicator of disease activity, particularly those with renal disease, as panel members pointed out.

Radiologic studies in turn are often obtained early in the evaluation of a patient with possible IgG4-RD but selection of the imaging modality that is most appropriate to the assessment of possible IgG4-RD is based on the organ under evaluation.

An IgG4-RD Responder Index has been developed as a quantitative means of assessing overall response to treatment, panel members observed, but no single means of assessing disease response is currently adequate for all patients with IgG4-RD.

Almost all panel members agreed that diagnostic confirmation by biopsy should be strongly recommended in order to exclude malignancies and other IgG4-RD mimics.

This is especially important given that results from clinical assessment, laboratory evaluation, and imaging studies are frequently insufficient to distinguish tumefactive lesions of IgG4-RD from cancer, as they note.

Needle biopsy is usually inadequate for the histopathologic diagnosis of IgG4-RD but generally yields quantities of tissue large enough to exclude malignancy with some confidence, the panel adds.

Indeed, a subset of patients with asymptomatic IgG4-RD also requires treatment because subclinical disease can lead to severe, irreversible sequelae in the biliary tree, kidney, aorta, mediastinum, and other organs.

Urgent treatment may include a combination of glucocorticoids at moderate to high doses, as well as mechanical interventions in specific organs such as stents for the biliary tract.

Rituximab may also be appropriate in some cases if glucocorticoids are contraindicated.

On the other hand, "watchful waiting" may be appropriate for patients with, for example, asymptomatic lymphadenopathy or mild submandibular gland enlargement.

"Treatment leads to faster and more complete remission with fewer long-term complications of IgG4-RD than does wait to treat," panel members caution.

"Treatment is therefore justified in most cases in which laboratory or radiology findings suggest organ dysfunction."

As panel members note, in some patients, symptoms reflect fibrotic "burnt-out" disease as opposed to active IgG4-RD and longstanding highly fibrotic lesions may respond poorly if at all to currently available agents.

In such patients, the risk to benefit balance therefore may not favor repeated courses of treatment.

Surgical debulking may be an option for IgG4-RD involvement but it depends on the anatomic region the disease has affected and the adjacent structures involved.

Panel members also universally agreed that glucocorticoids should be the first-line agent for remission induction in all patients with active untreated IgF4-RD unless contraindications are present.

Prednisone at a dose of 30 to 40 mg a day is commonly used although the dose may be adjusted based on body weight and aggressivity of the disease.

The initial glucocorticoid dose should be maintained for 2 to 4 weeks, panel members largely agreed, after which it can be gradually tapered.

Only about half of the panel members agreed that some but not all patients require the combination of glucocorticoids and a steroid-sparing immunosuppressive agent from treatment onset.

As they point out, practice patterns for the treatment of IgG4-RD vary widely across countries and some members had no experience with the use of steroid-sparing agents of any kind.

However, most panel members did agree that the addition of a steroid-sparing agent is appropriate when the glucocorticoid dose cannot be tapered down due to persistently active disease.

In certain circumstances, providers may consider adding a steroid-sparing agent during induction therapy and continue the agent as maintenance therapy as well.

Azathioprine, mycophenolate mofetil, 6-mercaptopurine, methotrexate tacrolimus, and cyclophosphamide have all been used by various investigators as steroid-sparing agents.

Data supports the use of B cell depletion as a valid steroid-sparing approach as well and rituximab may also be considered where available and indicated.

Following a successful course of induction therapy, most panel members agreed that certain patients still benefit from maintenance therapy.

For example, patients with organ-threatening IgG4-RD manifestations and those with an elevated risk of relapse will likely benefit from maintenance therapy to minimize morbidity.

Maintenance therapy may consist of low-dose glucocorticoids or any of the steroid-sparing agents that might have been used for induction therapy.

"Regardless of the agent used, the optimal duration of maintenance therapy has not been evaluated rigorously and probably depends on a number of patient-specific factors," panel members observe.

"And retreatment with glucocorticoids is indicated in patients who relapse off treatment following successful remission induction."

Once a patient relapses, initiation of a steroid-sparing agent should again be considered and used during the remission maintenance period.

Panel members also note that the vast majority of patients who experience IgFG4-RD flares respond well to glucocorticoid-based strategies.

"The consensus among experts in IgG4-RD is that the threshold for initiating treatment in patients with active disease is low," they state.

"Irreversible injury to some organs can occur within weeks or months if effective therapy is not initiated and the prevention of fibrosis and it's potentially destructive impact on organs is a major aim of treatment," they add.

"Once fibrosis is established, therapeutic options are currently limited."

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